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Sustained calcium signalling and caspase-3 activation involve NMDA receptors in thymocytes in contact with dendritic cells.

ABSTRACT: L-glutamate, the major excitatory neurotransmitter, also has a role in non-neuronal tissues and modulates immune responses. Whether NMDA receptor (NMDAR) signalling is involved in T-cell development is unknown. In this study, we show that mouse thymocytes expressed an array of glutamate receptors, including NMDARs subunits. Sustained calcium (Ca(2+)) signals and caspase-3 activation in thymocytes were induced by interaction with antigen-pulsed dendritic cells (DCs) and were inhibited by NMDAR antagonists MK801 and memantine. NMDARs were transiently activated, triggered the sustained Ca(2+) signal and were corecruited with the PDZ-domain adaptor postsynaptic density (PSD)-95 to thymocyte-DC contact zones. Although T-cell receptor (TCR) activation was sufficient for relocalization of NMDAR and PSD-95 at the contact zone, NMDAR could be activated only in a synaptic context. In these T-DC contacts, thymocyte activation occurred in the absence of exogenous glutamate, indicating that DCs could be a physiological source of glutamate. DCs expressed glutamate, glutamate-specific vesicular glutamate transporters and were capable of fast glutamate release through a Ca(2+)-dependent mechanism. We suggest that glutamate released by DCs could elicit focal responses through NMDAR-signalling in T cells undergoing apoptosis. Thus, synapses between T and DCs could provide a functional platform for coupling TCR activation and NMDAR signalling, which might reflect on T-cell development and modulation of the immune response.

SUBMITTER: Affaticati P

PROVIDER: S-EPMC3131881 | biostudies-literature | 2011 Jan

REPOSITORIES: biostudies-literature

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Sustained calcium signalling and caspase-3 activation involve NMDA receptors in thymocytes in contact with dendritic cells.

Affaticati P P Mignen O O Jambou F F Potier M-C MC Klingel-Schmitt I I Degrouard J J Peineau S S Gouadon E E Collingridge G L GL Liblau R R Capiod T T Cohen-Kaminsky S S

Cell death and differentiation 20100625 1

L-glutamate, the major excitatory neurotransmitter, also has a role in non-neuronal tissues and modulates immune responses. Whether NMDA receptor (NMDAR) signalling is involved in T-cell development is unknown. In this study, we show that mouse thymocytes expressed an array of glutamate receptors, including NMDARs subunits. Sustained calcium (Ca(2+)) signals and caspase-3 activation in thymocytes were induced by interaction with antigen-pulsed dendritic cells (DCs) and were inhibited by NMDAR an ...[more]

PMID: 20577261

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Project description:Neurons, represented as a tree structure of morphology, have various distinguished branches of dendrites. Different types of synaptic receptors distributed over dendrites are responsible for receiving inputs from other neurons. NMDA receptors (NMDARs) are expressed as excitatory units, and play a key physiological role in synaptic function. Although NMDARs are widely expressed in most types of neurons, they play a different role in the cerebellar Purkinje cells (PCs). Utilizing a computational PC model with detailed dendritic morphology, we explored the role of NMDARs at different parts of dendritic branches and regions. We found somatic responses can switch from silent, to simple spikes and complex spikes, depending on specific dendritic branches. Detailed examination of the dendrites regarding their diameters and distance to soma revealed diverse response patterns, yet explain two firing modes, simple and complex spike. Taken together, these results suggest that NMDARs play an important role in controlling excitability sensitivity while taking into account the factor of dendritic properties. Given the complexity of neural morphology varying in cell types, our work suggests that the functional role of NMDARs is not stereotyped but highly interwoven with local properties of neuronal structure. Author summary A single neuron receives a large number of inputs from its dendrites. A fundamental principle for neural dynamics is how these inputs are collectively integrated and converged to the neuronal soma to generate diverse patterns of action potentials. Such a principle has been formulated as a question of dendritic integration, which depends on the biophysical properties of neuronal dendrites and their associated synapses. It has been documented that NMDA plays an important role in dendritic integration. However, it remains unclear how dendritic integration is related to the distribution of NMDA receptors on various parts of the dendritic morphology of a neuron. Here we use Purkinje cell as a model system to symmetrically investigate this question, as the Purkinje cell exhibits a mixture of simple and complex spikes. By exploring the role of NMDA at different parts of dendritic branches and regions, we found somatic responses are diverse from simple to complex spikes, depending on specific dendritic branches. Our results suggest that the functional role of NMDA is highly interplayed with the local properties of neuronal dendrites.

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Sustained calcium signalling and caspase-3 activation involve NMDA receptors in thymocytes in contact with dendritic cells.

Publications

Sustained calcium signalling and caspase-3 activation involve NMDA receptors in thymocytes in contact with dendritic cells.

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